The use of bone morphogenic proteins (BMPs) shows promise as therapeutics for improving bone regeneration; however, high supraphysiological concentrations required for desired osteoinductive effect, costs, and patient variability have prevented the full advantages of BMP-based therapeutics from being realized. Thus, there is a clinical need to develop growth factor delivery strategies that will optimize release kinetics and overcome the need for non-physiologic high concentrations to promote bone repair. The proposed approach utilizes a matrix metalloprotease (MMP)-sensitive hyaluronic acid (HA)-based hydrogel scaffold as a cell-mediated delivery vehicle, where the remodeling of the gel releases the molecules. Scaffold degradation kinetics can be controlled through varying the MMP sensitivity of the proteolytic peptide and through cross-link density. Canonical Wnt signaling is known to promote osteoblastogenesis, osteoblast function, and bone regeneration and can be promoted using the R-spondin (Rspo) family of secreted molecules. Enhancing canonical Wnt signaling through the synergistic delivery of BMP2 and Rspo2 using an engineered synthetic HA-based hydrogel should allow for improved bone tissue repair. With these features in mind, the objective of this work is two-fold: (1) evaluate the influence of hydrogel remodeling and BMP2 growth factor release kinetics on in vivo tissue repair and (2) determine if the synergistic delivery of Rspo2 and BMP2 improves BMP2 induced osteogenesis. Growth factor release kinetics and bioactivity will be evaluated using in vitro characterization techniques. A cranial defect rat model will be used to determine the influence of both growth factor release profiles and the combined delivery of Rspo2 and BMP2 on bone tissue formation. Thus, the specific aims of the work are: (1) Determine the effect of BMP2 release kinetics on osteogenesis (a) in vitro and (b) in vivo using MMP-sensitive hydrogels of varying sensitivity and (2) Synergistic delivery of Rspo2 and BMP2 for improved bone tissue repair. Upon completion of this work, a more thorough understanding of BMP-based therapies will be obtained, as well as work towards a clinically translatable approach to improve the treatment of patients with bone loss.